IE46358B1 - W-aryl-13-prostynoic acid derivatives - Google Patents

Abstract

The invention relates to new compounds of formula: [FR2375208A1]

Description

The present invention relates to ω-aryl-13-prostynoic acid derivatives and salts thereof, to a process for their preparatiop, to pharmaceutical formulations containing them and to their use as antifertility agents.

The present invention provides in one aspect a compound of formula (I) HO R' wherein R is a hydrogen atom or an alkyl group having from 1 to 7 carbon atoms; Y is a group -CH2-CH2- or eis-CH=CH-; 10 R', R" and R' are the same or different and each is a hydrogen atom or a methyl group; n is from 0 to 3; and Ar is a phenyl, a halosubstituted phenyl, a lower alkylsubstituted phenyl wherein the lower alkyl contains from 1 to 4 carbon atoms, a lower alkoxy substituted phenyl wherein the lower alkoxy contains from 1 to 4 carbon atoms, a £-biphenylyl; or a trifluoromethyl substituted phenyl group; and the wavy lines represents R or s stereochemistry 6 3 5 8 and when R is a hydrogen atom, the salts thereof. The symbol X (-) as used herein and throughout the specification refers to both the compound shown and also to its mirror image with regard to the stereochemistry about the 1,2 and 3 positions of the 5 membered ring, i.e. α, β, β and β, a, a.

An alkyl group having from 1 to 7 carbon atoms .refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl groups and branched chain isomers thereof.

The term lower alkyl substituted phenyl refers to, for example, tolyl, ethylphenyl, ^-tertiary butylphenyl, and £-propylphenyl.

Halo substituted phenyl refers to, for example, chlorophenyl, fluorophenyl, bromophenyl, and iodophenyl.

Alkoxy substituted phenyl refers to, for example, methoxyphenyl, ethoxyphenyl, propoxyphenyl, and butoxyphenyl.

Preferred compounds are those of formula (II), which compounds fall wholly within the scope of formula (I), wherein (+) co2r R (II) Wn' Ar OH R' wherein R, R , R, R', n and Ar are as hereinbefore defined. Particularly preferred compounds are those of formula (III), which compounds fall wholly within the scope of formula (I), wherein (III) R and Ar are as previously defined.

Compounds of the present invention may be prepared by reacting a compound of formula (IV) (ch2)3_ co2r (IV) wherein R and Y areas hereinbefore defined, with a dimethyl(ω-aryl-l-alkynyl)aluminium compound of formula (V) Si(Alk), I 3 R - 0 T Ar-(CH_) 0 - C - C == C-A1(CH, )' η, ι 3 2 R' R' wherein Ar, R1, R, R', and n are as previously defined; 10 and Alk is an alkyl having from 1 to 4 carbon atoms; followed by hydrolysis of the trialkylsilyl protecting group and subsequent chromatographic separation of thus obtained compounds. - 5 Thus, according to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I) or when R is a hydrogen atom the salts thereof, (+) CH.-Y ' 2 .(CH2)3-C°2R R' R (I) HO C—C — C —C -(CH.) -Ar n > HO R’ wherein R, Y, R', R, R', n and Ar are as hereinbefore defined which comprises the steps of (i) reacting a compound of formula (IV): ch2—Y .(^)3-00^ (IV) wherein R and Y are as hereinbefore defined with a compound of formula (V) Si(Alk).

Ar - (CH.) n R 0 I I C - C - C Ξ= C I 1 R R1 A1(CH3)2 463 58 wherein Ar, R'-, R, R' and n are as hereinbefore defined and Alk is an alkyl group having from 1 to 4 carbon atoms, (ii) removing the trialkylsilyl protecting group byhydrolysis,· (iii) chromatographically separating the reaction products;. and (iv) optionally converting compounds of formula (I) having R as a hydrogen atom into the salts thereof.

The dimethyl (ω-aryl-l-alkynyl)aluminium starting 10 materials of formula (V) may be prepared by the method set out in Scheme 1: - 7 ✓46 3 38 § ffi O υ »rl hJ ffi υ rH u •H ω □ I . • □ —tf Al rH η O II ri! CJ Μ I tc I o —u _> pj — o — 04 •ffi ffi o ffi □ tf H >t Λ υ ό «i| CJ td >S ffi SS CN Pi I = 0 ffi rH ri! Bi-O -ffi k ri! ri! a rH tf M ω a rH tf -O-O —ffi ffi —O' ffi o k ri! . - a The starting materials for the preparation of compounds depicted in Scheme.I are exemplified for instance by ketones and aldehydes of the formula (VI) R li I R' - C - C - ( CH ) - Ar (VI) | 2 n R' Ar n R R1 R7_ phenyl 1 H HCH3 m-chlorophenyl 1 H HCH3 £-fluorophenyl 1 H HCH3 m-trifluoromethylphenyl 1 . H ff -CH3 10 phenyl _ 1 ch3CH3 H phenyl 2 H H CHs phenyl 0CH3CH3 H phenyl . 3 H HCH3 phenyl 2 HCH3CL!3 15 p-metho:ryphenyl 1 H HCH3 £-methylphenyl 1 H H ch3 £-ethylphenyl 1 H HCH3 biphenylyl 1 H HCK3 Carboxylic’ acids may be converted to the above and-aldehydes by techniques recognised in the art.

Methyl 7-(3-hydroxy-5-oxo-l-cyclopenten-l-yl)heptanoate, methyl 7-(3"hydroxy"5"Oxo-l-cyclopenten-l-yl)hept-5ciB-enoate and their corresponding acids are known starting materials. Example 1 illustrates a preferred method of preparing compounds of the present invention.

The closest prior art appears to be U.S. Patent No. 3,973,440 which describes PGEg analogs of the formula: - 9 46358 These compounds differ from compounds of the present invention in the stereochemistry at C-ll and in having a -CH=CH- at C, --C, . instead of -CSC-. The 11-Deoxy 13 14 compounds of the present invention are disclosed in Belgian Patent 839,533, and U.S, Patent 3,978,114 also discloses related compounds.

Tetrahedron Let. 26, page 2627 (1972) describes compouhds of the formula: Compounds of the present invention are particularly distinct from these in that there is a phenyl substituted alkyl radical in place of -CgH^.

The antifertility activity of the present compounds 15 of the present invention may be illustrated by the following test* - 10 Sexually mature 9-10 weeks old female Syrian Golden hamsters are caged with males in the late afternoon. Vaginal· smears are taken daily between 8.15 and 10.00 a.m. by means of a pipette, and the presence of sperm is oonsid5 ered positive evidence of insemination. The day of insemination is designated as day 1 of pregnancy. Pregnant females are injected daily with the test compound beginning on day 1 to day 5. Route of administration may be either subcutaneous or intragastric. The daily injection is usually in a volume of 0.2 cc corn oil, but the volume and vehicle may vary depending on the physical characteristics of the particular compound being tested. All animals are sacrificed with dry ioe (C02) on the morning of day 6.

The entire reproductive tract is then removed and the uterus and ovaries trimmed of extraneous tissue. The total number of implantation sites is counted and recorded. By observation, day 6 size sites are designated as normal and any sites which are smaller and/or pale or resorbing are designated as abnormal.

The total number of corpora lutea are counted and recorded. By observation, the red corpora are considered normal and the pale, pink or white regressed corpora are considered abnormal.

A single dose of compound is classified as active or inactive on the basis of the percent implantation, which is found by dividing the total number of implantation sites by the total number of corpora lutea and then multiplying by 100. 50% or less implantation rate is considered active. 51% of more implantation rate is considered inactive. 463S8 Abnormal implantation sites and corpora lutea are also reported either when 20% or more sites are abnormal or in the case of when there are no abnormal sites, when only 50% or more abnormal corpora lutea are present. The ΕΟ^θ of a compound is either approximated from inspection or calculated according to the method of Berkson (J. Amer.

Stat. Assoc. 48 (253); 565, 1953). Estrone is employed as the standard. A relative potency is obtained from the ratio of the ED„ of Estrone to that of the test compound.

Racemic methyl 7-[3β-hydroxy-2β-(3(S)-hydroxy-3methyl-5-pheny1-1-pentyn-l-yl)-5-oxocyclopent-la-yl] -heptanoate, a representative compound of the present invention, is active in the hereinbefore described antifertility test at 50-200 mg. per hamster.

Compounds and pharmaceutically acceptable salts thereof of the present invention may be combined with common pharmaceutical carriers to produce pharmaceutical formulations. These formulations and also the compounds can be administered either orally or parenterally. Por oral administration tablets, lozenges, capsules, dragees, pills or powders are suitable, while aqueous solutions, non-aqueous solutions or suspensions are appropriate for parenteral administration. Acceptable pharmaceutical carriers are exemplified by gelatin capsules, sugars such as lactose or sucrose, starches such as corn starch or potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose or cellulose acetate phthalate, gelatin, talc, calcium phosphate, such as dicalcium phosphate or tricalcium phosphate, sodium sulfate, calcium sulfate, polyvinylpyrrolidone, acacia, polyvinyl alcohol, stearic acid, alkaline earth metal stearates such as magnesium stearate, vegetable 3 5 8 - 12 oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil or ..theobroma, water, agar, alginic acid, benzyl alcohol, isotonic saline and phosphate buffer solutions as well as other non-toxic compatible substances.

The invention will be illustrated more fully from the . following non-limiting Examples.

In the Examples, temperatures are given in degrees Centigrade (°C) and quantity of materials in parts by weight unless parts by volume is specified. The relationship between parts by weight and parts by volume is the same as that existing between grams and milliliters. Nuclear magnetic resonance spectra were determined on a 60- or a 100-mega Hz. instrument and are indicated in parts per million (fi).

Example 1 Parts by volume of 2.5 molar n-butyl lithium was added to a solution of 3.1 parts of triethylsilylacetylene in 20 parts by volume of diethyl ether at -30°. The resulting solution was allowed to warm to room temperature.

It was then cooled again to -30° and 3 parts of 4-phenyl-2butanone was added. The reaction mixture was allowed to return to room temperature and was then stirred for I hour. The reaction mixture was poured into a mixture of diethyl ether and dilute hydrochloric acid. The ethereal layer was washed with water and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure and the residual oil was dissolved in 15 parts by volume of dimethylformamide containing 2 parts of powdered potassium fluoride. This reaction mixture was stirred and heated at 70-80° for 1 hour, after which time It was diluted with water and extracted with ether. The ether layer was separated and washed with water and dried over - 13 anhydrous sodium sulfate. The ether was removed under reduced pressure and the residue was chromatographed on silica gel using 30% ethyl aeetate/hexane as eluant to provide 3-methyl-3-hydroxy-5-phenyl-l-pentyne.

The hydroxyl group of 3-methyl-3-hydroxy-5-phenyl-1pentyne was protected by treating 3.6 parts of the compound in 15 parts by volume of dimethylformamide successively with 3.5 parts of imidazole and 4.0 parts of triethylsilyl chloride and stirring the resulting mixture for 1 hour at room temperature. The reaction mixture was poured into diethyl ether/water and the ethereal layer was washed with water three times, dried over anhydrous sodium sulfate, and the ether was then removed at reduced pressure. Distillation of the residual oil provided 3-methyl-5-phenyl3-triethylsilyloxy-l-pentyne.

To 1.74 parts of this ether in 10 parts by volume of diethyl ether at -40° was added 2.8 parts by volume of 2.17 molar butyl lithium. The resulting reaction mixture was allowed to stand at room temperature for 30 minutes and then was cooled again to -40°. A solution of 3.7 parts of a 15% by weight solution of dimethylaluminium chloride in hexane was added, and the reaction mixture was allowed to come to room temperature. The resulting reaction mixture containing dimethyl(3-methyl-5-phenyl-3triethylsilyloxy-l-pentyne)aluminium was then treated with 1 part of methyl 7-(3-hydroxy-5-oxo-l-cyclopenten-l-yl)heptanoate in 10 parts by volume of diethyl ether. The reaction mixture was stirred at room temperature for 1-2 hours and poured into diethyl ether and 1 N hydrochloric acid. The ethereal layer was separated, washed with water, and dried over anhydrous sodium sulfate. Subsequently the ether was removed at reduced pressure. Purification - 14 of the residual oil by low pressure liquid chromatography on silica gel using 30% ethyl acetate/hexane as eluant provided the intermediate, methyl 7-[3p-hydroxy-2p~(3methyl-3-tyiethylsilyloxy-5-phenyl-1 -pentyn-1-yl)-5-oxo5 cyclopent-la-yl] heptanoate. This material was hydrolyzed - overnight at room temperature using a 3/1/1 acetic acid/ water/tetrahydrofuran mixture. The reaction mixture was diluted with diethyl ether, washed 6 times with water, dried over anhydrous sodium sulfate, and the solvent was. then removed. Low pressure liquid chromatography on silica gel using 100% ethyl acetate as eluant provided racemic methyl 7-[3p-hydroxy-2p-(3(R)-hydroxy-3-methyl-5-phenyl-lpentyn-l-yl)-5-oxocyclopent-la-yl]heptanoate and racemic methyl 7[3p-hydroxy-2p-(3 (S.)-hydroxy-3-methyl-5-phenyl-115 pentyn-l-yl)-5-oxocyclopent-lra-yl]heptanoate.the latter characterized by nuclear magnetic resonance spectrum peaks at approximately δ 1.56, 53.66 and δ7.21.

Example 2 m-Trifluoromethylcinnamic acid was hydrogenated at room temperature at 2 psi using palladium! on carbon as catalyst to provide m-trifluoromethyl hydrocinnamic acid. 21.8 Parts of this acid was dissolved in 200 parts by volume of diethyl ether. 1OO Parts by volume of 1.0 molar methyl lithium in diethyl ether was then added dropwise over a 30-minute period at o°. After the addition was complete the mixture was stirred at room temperature for 3-4 hours. The mixture was poured into 1 N HCl, the organic layer was washed successively with water and 5% potassium carbonate, and it was then dried over anhydrous sodium sulfate. The solvent was removed to provide 4-(mtrifluoromethyl phenyl)-2-butanone. Following the procedure set out in Example 1, replacing 4-phenyl-24 63 58 butanone with 4-(m-trifluoromethyl phenyl)-2-butanone, provided racemic methyl 7-(3p-hydroxy-2p-[3(R)-hydroxy-3methyl-5-(m-trifluoromethylpheny1)-1-pentyn-l-yl]-5-oxocyclopent-la-yl]heptanoate and racemic methyl 7-[3phydroxy-2 β- [ 3 (S.) -hydroxy-3 -methyl -5 - (m-tr if 1 uoromethyl phenyl)-1-pentyn-l-yl]-5-oxocyclopent-la-yl]heptanoate, which latter compound is characterized by nuclear magnetic resonance spectrum peaks at approximately 51.59, 63.68, and 64.47.

In a similar manner to the above p-trifluorocinnamic acid was converted to racemic methyl 7-[3p-hydroxy-2p[3(£3)-hydroxy-3-methyl-5-(p-fluorophenyl)-1-pentyn-l-yl] -5oxoeyelopent-la-yl] heptanoate, and the racemic 3R derivative thereof; p-bromocinnamic acid was converted to racemic methyl 7-[3p-hydroxy-2p-[3(S.)-hydroxy-3-methyl-5(p-bromophenyl)-1-pentyn-l-yl] -5-oxocyclopent-la-yl] heptanoate, and the racemic 3R derivative thereof; m-chlorocinnamic acid was converted to racemic methyl 7-[3p-hydroxy2 p-[3(S)-hydroxy-3-methyl-5-(m-ohlorophenyl)-1-pentyn-1-yl]5-oxooyclopent-la-yl]heptanoate, characterized by nuclear magnetic resonance spectrum peaks at approximately 62.0, 2.84, and 6 3.67, and the racemic 3R derivative thereof characterized by nuclear magnetic resonance spectrum peaks at approximately 6 1.57, 6 3.7, and 64.44? p-methylcinnamic acid was converted to racemic methyl 7-[3p-hydroxy-2p[ 3 (S.) -hydroxy-3 -methyl -5- (p-methyl -phenyl) -1 -pentyn-1 -yl] 5-oxocyclopent-la-yl]heptanoate, and the racemic 3R derivative thereof; p-ethylcinnamic acid was converted to racemic methyl 7-[3p-hydroxy-2p-(3(s)-hydroxy-3-methyl-5(p-ethylphenyl)-1-pentyn-l-yl] -5-oxocyclopent-la-yl] heptanoate, and the racemic 3R derivative thereof? p-methoxycinnamic acid was converted to racemic methyl 7-[3p-hydroxy-16 ,1 ΰ 3 5 8 β- [3 (S) -hydroxy-3-methyl -5-(p_-methoxyphenyl) -1-pentyn-lyl]-5-oxocyclopent-la-yl]heptanoate, characterized by nuclear magentic resonance spectrum peaks at approximately 61.57, 63.68 and 64,46, and the racemic 3R derivative thereof; and p-phenylcinnamic acid was converted to racemic methyl 7-[3p-hydroxy~2p-(3-(i3)-hydroxy-3-riiethyl-5-g.biphenylyl-l-pentyn-l-yl)-5-oxocyclopent-la-yl]heptanoate, and the racemic 3R derivative thereof. 4-Phenylbutyric acid was converted to racemic methyl10 7-[3p-hydroxy-2p-{3(S)-hydroxy-3-methyl-6-phenyl-l-hexyn-lyl)-5-oxocyclopent-la-yl]heptanoate characterized by nuclear magnetic resonance spectrum peaks at approximately 61.50, 62.75, and 63.68, and the 3R derivative thereof.

Example 3 Following the procedure of Example I, but replacing 4-phenyl-2-butanohe with 2,2-dimethyl-3-phenyl-propionaldehyde, provided racemic methyl 7-[3β-hydroxy-2β-(3(R)-hydroxy-4,4-dimethyl-5-phenyl-l-pentyn-l-yl)-5-oxocyclopent-la-yl ] -heptanoate and racemic methyl 7-[3p-hydroxy20 2β-(3(£)-hydroxy-4,4-dimethyl-5-phenyl-1-pentyl-l-yl)-5oxocyclopent-la-yl)heptanoate, Example 4 Following the procedure of Example 1 using 4-phenyl-2butanone and methyl 7-(3-hydroxy-5-oxo-1-cyclopent-1-yl) 25 hept-5-cls-enoate provided racemic methyl 7-[3p-hydroxy-2p(3(RS)-hydroxy-3~methyl-5-phenyl-l-pentyn-l-yl/-5-oxpcyclopent-la-yl]hept-5-cls-enoate characterized by nuclear magnetic resonance spectrum peaks at approximately 61.58, fi 2.82 and <5 4 .48.

Example 5 Following the procedures of Examples 1 and 2 using m-chlorophenylacetone and racemic 7-(3-hydroxy-5-oxo-l46338 cyclopenten-l-yl)heptanoate, provided racemic methyl 7-[3βhydroxy-2p-[3(S)-hydroxy~3-methyl-4-(m-chlorophenyl)-1butyn-l-yl]-5-oxocyclopent-la-yl] heptanoate characterized by nuclear magnetic resonance spectrum peaks at approximately δΐ.57, δ2.96, and 63.69, and the 3(R) stereoisomer thereof.

Example 6 Substituting 7-(3-hydroxy-5-oxo-l-cyclopenten-l-yl)heptanoic acid, ethyl 7-(3-hydroxy-5-oxo-l-cyclopenten-lyl)heptanoate and heptyl 7-(3-hydroxy-5-oxo-l-cyclopenten1-yl)heptanoate, respectively for methyl 7-(3-hydroxy-5oxo-1-cyclopenten-l-yl)-heptanoate used in Example 1 and substantially repeating the procedure detailed in that Example, the following compounds were obtained: racemic 7-[3p-hydroxy-2β—(3(S)-hydroxy-3-methyl-5-phenyl-1-pentynl-yl )-5-oxoeyclopent-la-yl] heptanoic acid, and the racemic 3R derivatives thereof; racemic ethyl 7-[3P-hydroxy-2p(3 (S.) -hydroxy-3 -methyl -5-phenyl-l-pentyn-l-yl)-5-oxocyelopent-la-yl]heptanoate, and the racemic 3R derivative thereof; and racemic heptyl 7-[3p-hydroxy~2p-(3(!5)-hydroxy3-methyl-5-phenyl-1-pentyn-l-yl)-5-oxocyclopent-la-yl] heptanoate, and the racemic 3R derivative thereof.

Example 7 Following the procedure of Example 1, using 4-(mtrifluoromethyl phenyl)-2-butanone and methyl 7-(3-hydroxy5-oxo-l-cyclopenten-l-yl)hept-5~cis-enoate, provided racemic methyl 7-[3p-hydroxy-2 p- [ 3 (S.) -hydroxy-3-methyl-5(m-trifluoromethyl-phenyl)-1-pentyn-l-yl]-5-oxocyclopentla-yl] hept-5-cis-enoate, and the racemic 3R derivative thereof.

Example 8 Following the procedures of Examples 1 and 2 using m-chlorocinnamic acid and methyl 7-(3-hydroxy-5-oxo-1cyclopenten-l-yl)hept-5-cis-enoate, provided racemic methyl 7-[3p-hydroxy-2p-[3(Sj-hydroxy-3-methyl-5-(m-chlorophenyl) 1-pentyn-l-yl]-5-oxocyclopent-la-yl]hept-5-cis-enoate. and the racemic 3R derivative thereof.

Example 9 Following the procedures of Examples 1 and 2 using ja-methoxycinnamic acid and methyl 7-(3-hydroxy-5-oxo-lcyclopenten-l-yl)hept-5-cis-enoate, provided racemic methyl 7-[3p-hydroxy-2p-[3 (S.) -hydroxy-3-methyl-5-(]o-methoxyphenyl)1-pentyn-l-yl] -5-oxocyclopent-la-yl]hept-5-cis-enoate and the racemic 3R derivative thereof.

Example 10 Following the procedures of Examples 1, 2 using 5phenylpentanoic acid and methyl 7-( 3-hydroxy-5-oxo-1cyclopenten-l-yl)heptanoate, provided racemic methyl 7-[3βhydroxy-2β — (3 (S.)-hydroxy-3-methyl-7-phenyl-1-heptyn-1-yl)20 5-oxocyclopent-la-yl] heptanoate, and the racemic 3R derivative thereof.

Example 11 Described below are typical pharmaceutical formulations containing the compounds of this invention.

Tablet Ingredient Racemic methyl 7-[3β-hydroxy-2β(3(S)-hydroxy-3-methyl-5-phenyl5 1-pentyn-l-yl)-5-oxocyclopent-layl]heptanoate Amount (mg.)/Tablet 0.001 Mannitol 36.00 Microcrystalline Cellulose 10.00 Polyvinylpyrrolidone 2.50 Thixcin 1.50 The active ingredient is dissolved in isopropyl alcohol and distributed on mannitol. The mixture is airdried and passed through a 40 mesh screen. Microcrystalline cellulose and polyvinylpyrrolidone are added to the mixture, mixed thoroughly and passed through a 40 mesh screen. The mixture is then granulated with isopropyl alcohol, spread on trays, and dried at room temperature for 4 hours. The dried granulation is then screened.

The granules are mixed thoroughly with thixin and the mixture compressed into tablets.

Capsule Ingredient Racemic methyl 7-[3p-hydroxy-2p(3(S)-hydroxy-3-methyl-5-phenyl25 1-pentyn-l-yl)-5-oxocyclopent-layl]-heptanoate Amount (mg.)/Capsule 0.001 Mannitol 140.00 Microcrystalline Cellulose .00 - 20 The active ingredient is dissolved in isopropyl alcohol and distributed on mannitol. Microcrystalline cellulose is added and the mixture is thoroughly mixed and filled into the appropriate hard gelatin capsule by hand or machine using 175 mg. fill per capsule.

It should be understood that any of the compounds or pharmaceutically acceptable salts thereof of formula (1) may be used in the formulation of the invention.

Other acceptable pharmaceutical carriers for use in the above formulations are exemplified by sugars such as lactose, sucrose, mannitol, or sorbital; starches such as corn starch, tapioca starch, or potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, or methyl cellulose; gelatin;> calcium phosphates such as dicalcium phosphate or tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate; stearic acid vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil; surfactants (nonionic, cationic, anionic); ethylene glycol polymers; beta-cyclodextrin; fatty alcohols; hydrolyzed cereal solids; as well as other ηόη-toxie compatible fillers, binders, disintegrants, and lubricants commonly used in pharmaceutical formulations.

Parenteral Ingredient Amount (mg.)/2cc.

Racemic methyl 7-[3g-hydroxy-2p(3(s)-hydroxy-3-methyl-5-phenyl1-pentyn-l-yl)-5-oxocyclopent-1ayl]heptanoate) Ethanol 0.001 2.0 6 3 5 8 - 21 The active ingredient is dissolved in the ethanol, the solution is filtered, and filled into ampoules and these are sealed. Sterilization of the ampoules is achieved by an appropriate sterilization procedure.

Other acceptable pharmaceutical carriers for a parenteral product are exemplified by vegetable oils such as peanut oil, corn oil, cottonseed oil, and sesame oil; benzyl alcohol, saline, phosphate buffer, water, ethylene glycol polymers, urea, N-N-dimethylacetamide, Triton (Registered Trade Mark), dioxolanes, ethyl cargonate, ethyl lactate, glycerol formal, isopropyl myristate, surfactants (nonionic, cationic, anionic), polyhydric alcohols, and ethanol.

In the formulations of the type described above, the novel compounds of this invention are present in an amount envisioned to produce the desired effect. Although 0.001 mg, per unit dose is often convenient, considerably more or less active ingredient can be incorporated into each dosage unit if so desired. The daily dosage of these compounds is dependent upon various factors such as the particular compound employed, the condition for which the compound is administered and the patient's individual response.

Claims (14)

1. CLAIMS i 1. A compound of formula (I) wherein R is a hydrogen atom or an alkyl group having from 1 to 7.carbon atoms; Y is a group -ΟΗ,,-αΐ,,- Or cis-CH=CH-; R', R, and R* are the same or different and each is a hydrogen atom or a methyl group? n is from 0 to 3; and Ar is a phenyl, a halosubstituted phenyl, a lower alkyl substituted phenyl wherein the lower alkyl group contains from 1 to 4 carbon atoms, a lower alkoxy substituted phenyl wherein the lower alkoxy group contains from 1 to 4 carbon atoms, a 33-biphenylyl, or a trifluoromethyl substituted phenyl and the wavy line, represents R or S stereochemistry and when R is a hydrogen atom,the salts thereof.

2. A compound as claimed in claim 1 wherein Y is a group -CH 9 -CH 2 - and n, R, R', R lr , R' and Ar are as hereinbefore defined.

3. A compound as claimed in claim 2 wherein Y is a group -CH 2 ~CH 2 -. n is 1, R“ and R' are the same and each is a hydrogen atom and R, R' and Ar are as hereinbefore defined.

4. Racemic methyl 7-[3p-hydroxy-23-(3(iS)-hydroxy-3methyl-5-phehyl-1-pentyn-l-yl) -5-oxocyclopent-la-yl] heptanoate. 46338 - 23 5. Racemic methyl 7-[3p-hydroxy-2p-(3(S)-hydroxy-3methyl-5-(m-trifluoromethylphenyl)-1-pentyn-l-yl)-5-oxocyclopent-la-yl] heptanoate. 6. Racemic methyl 7-[3 p-hydroxy-2 p-( 3 (S.) -hydroxy-35 methyl-5-(m-chlorophenyl)-1-pentyn-l-yl)-5-oxocyclopent-layl] heptanoate. 7. Racemic methyl 7-[3p-hydroxy-2p-(3(R)-hydroxy-3methyl-5-(m-chlorophenyl)-1-pentyn-1-yl)-5-oxocyclopent-1ayl]heptanoate. 10 8. Racemic methyl 7-[3p-hydroxy-2p-(3(S)-hydroxy-3methyl-5-(p-methoxyphenyl)-1-pentyn-l-yl)-5-oxocyclopent-layl] heptanoate. 9. Racemic methyl 7-[3p-hydroxy-2p-(3(S)-hydroxy-3methyl-5-phenyl-l-hexyn-l-yl)-5-oxocyclopent-la-yl] 15 heptanoate. 10. Racemic methyl 7-f3P-hydroxy-28-(3(RS)-hydroxy-3methyl-5-phenyl-1-pentyn-l-yl)-5-oxocyclopent-la-yl]hept-5cis-enoate. 11. Racemic methyl 7-[3p-hydroxy-2p-[3(,S)-hydroxy-320 methyl -4 - (m-chlorophenyl) -1 -butyn-1 -yl] -5 ‘-oxocyclopent -1 ayl]heptanoate. 12. A process for the preparation of a compound as claimed in claim 1 which comprises the steps of (i) reacting a compound of formula (IV) wherein R and Y are as hereinbefore defined, with a compound of formula (V) 4 6 3 5 8 - 24 Ar-(CH-) -C 2 Ii , I c I R' Si(Alk) 3 c Ξ7 c-si(ca 3 ) 2 (v) wherein Ar y R', R”, R' and n are as hereinbefore defined; and Alk is an alkyl group having from 1 to 4 carbon atoms; (ii) removing the trialkylsilyl protecting group from the

5. Thus obtained compound by hydrolysis; (iii) chromatographically separating the reaction products; and (iv) optionally converting compounds of formula (I) having R as a hydrogen atom into salts thereof. 13. A process for the preparation of racemic methyl10 7-( 3p-hydroxy-2 (3-(3 (S.) -hydroxy-3 -methyl-5 -phenyl-1 -pentyn-lyl) -5-oxocyclopent-la-yl] heptanoate which comprises the steps of: _ (i) reacting methyl 7-(3-hydroxy-5-oxo-l-cyclopenten-lyDheptanoate with dimethyl (3-methyl-5-phenyl-3-triethyl15 silyloxy-l-pentyne)-aluminium; (ii) removing the triethylsilyl protecting group by hydrolysis and? (iii) chromatogtaphically separating the reaction products. 14. A process for the preparation of racemic methyl 20 7-[3 p-hydroxy-2 β-(3 (S)-hydroxy-3-methyl-5-(m-trifluoromethyl phenyl)-1-pentyn-l-yl)-5-oxocyclopent-la-yl] heptanoate which comprises the steps of: (!) reacting methyl 7-(3-hydrojy-5-oxo-1-cyclopenten-l-yl)heptanoate with dimethyl[3-methyl-3-triethylsilyloxy-5-(m-trifluoromethyl25 phenyl)-1-pentyne]-aluminium; (ii) removing the triethylsilyloxy protecting group from the thus obtained compound and (iii) chromatographically separating the reaction products. - 25 46358 15. A process for the preparation of racemic methyl 7-[3 β-hydroxy-2 β-(3(S)-hydroxy-3-methyl-5-(m-chlorophenyl)1-pentyn-l-yl)-5-oxocyclopent-la-yl]heptanoate, and racemic methyl 7-[3 p-hydroxy-2β-[3(R)-hydroxy-3-methyl-5-(m-chlorophenyl)-1-pentyn-l-yl]-5-oxocyclopent-la-yl]heptanoate which comprises the steps of (i) reacting methyl 7-(3hydroxy-5-oxo-1-cyclopenten-l-yl)heptanoate with dimethyl [5-(m-chlorophenyl)-3-methyl-3-triethylsilyloxy-l-pentyne]aluminium; (ii) removing the triethylsilyl protecting group by hydrolysis from the thus obtained compounds, and (iii) chromatographically separating the reaction products. 16. A process for the separation of racemic methyl

6. 7-[3 B-hydroxy-2 β-[3(S)-hydroxy-3-methyl-5-(p-methoxyphenyl) 1-pentyn-l-yl)-5-oxocyclopent-la-yl]heptanoate which comprises the steps of (i) reacting methyl 7-(3-hydroxy-5oxo-1-cyclopenten-1-yl)heptanoate with dimethyl[5-(pmethoxyphenyl)-3-methyl-3-tri ethyl-silyloxy-1-pentyne)aluminium; (ii) removing the triethylsilyl protecting group from the thus obtained compound and; (iii) chromatographically separating the reaction products. 17. A process for the preparation of racemic methyl 7-(3B~hyt3roxy-2p-(3(s)-hydroxy-3-methyl-6-phenyl-l-hexyn-lyl)-5-oxocyelopent-la-yl]heptanoate, which comprises the steps of (i) reacting methyl 7-(3-hydroxy-5-oxo-l-cyclopenten-l-yl)heptanoate with dimethyl(3-methyl-6-phenyl-3triethyl-silyloxy-l-hexyne)aluminium; (ii) removing the triethylsilyl protecting group from the thus obtained compound, and; (iii) chromatographically separating the reaction products. 18. A process for the preparation of racemic methyl 7 - f 3 3-hydroxy-2 β-(3(RS)-hydroxy-3-methyl-5-phenyl-1pentyn-l-yl)-5-oxocyclopent-la-yl]hept-5-cis-enoate which 4 6 3 5 8 - 26 comprises the steps of (i) reacting methyl 7-(3-hydroxy-5oxo-1-cyclo-penten-1-yl)hept-5-cis-enoate with dimethyl(3methyl-5-phenyl-3-triethylsilyloxy-1-pentyne) aluminium, (ii) removing the triethylsilyl protecting group from the 5 thus obtained compound, and; (iii) chromatographically separating the reaction products. 19. A process for the preparation of racemic methyl 7-[3p-hydroxy-2p-[3(S)-hydroxy-3-methyl-4-(m-chlorophenyl)1-butyn-l-yl]-5-oxocyclopent-la-yl]heptanoate which

7. 10 comprises the steps of (i) reacting methyl 7-(3-hydroxy-5oxo-1-cyclo-penten-l-yl)heptanoate with dimethyl[4-(mchlorophenyl)-3-methyl-3-triethylsilyloxy-l-butyne]aluminium; (ii) removing, the triethylsilyl protecting group from the thus obtained compound and; (iii) chromatographically

8. 15 separating the end products. .

9. 20. A pharmaceutical formulation containing one or more of the compounds of formula (I) or pharmaceutically acceptable salts thereof as claimed in claims 1 to 11 together with a pharmaceutically acceptable carrier. 20 21. A pharmaceutical formulation as claimed in claim 20 in unit dose form. 22. A pharmaceutical formulation as claimed in claim

10. 21 wherein the active ingredient is present in an amount of 0.001 mg. 25 23. A method of preparing a pharmaceutical formulation as claimed in claim 20 which comprises admixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

11. 24. A compound of formula (l) or salt thereof as 30 claimed in claims 1 to 11 whenever prepared by a process as claimed in claims 12 to 19. - 27 463 58

12. 25. A compound of formula (I) or salts thereof as claimed in claims 1 to 11 substantially as hereinbefore described with particular reference to Examples 1 to 10.

13. 26. A process as claimed in claims 12 to 19 substan5 tially as hereinbefore described with particular reference to Examples 1 to 10.

14. 27. A pharmaceutical formulation as claimed in claims 20 to 22 substantially as hereinbefore described with particular reference to Example 11.